Loss of GDE2 leads to complex behavioral changes including memory impairment

Background Alzheimer’s disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized. Results Here, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition. Conclusions Taken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration. Supplementary Information The online version contains supplementary material available at 10.1186/s12993-024-00234-1.

dynamics for males (B) and females (C) during 30 minutes of testing in the OF task for 7-monthold WT and Gde2KO mice.No effect of genotype or its interactions was detected (three-way mixed design ANOVA, Ps>0.05).(D-F) The same measures and analysis as in A-C for 16-month-old mice.Gde2KO male mice demonstrated higher motor activity (D, Fisher LSD post hoc P<0.0001) that was partially ameliorated as testing progressed (E).While Gde2KO female mice (D, F) showed a trend towards higher motor activity (Fisher LSD post hoc, P<0.033 pre-Bonferonni correction), this was not significant after Bonferroni correction (P > 0.05).(G-L) Analysis of distance traveled in Y maze task separated by sex.(G-I) Total distance (G) and dynamics for males (H) and females (I) during Y maze testing in 7-month-old mice.Gde2KO male and female mice were more active than WT mice during trial 2 (ANOVA, effect of genotype F(1,≥24)>18.18,P<0.0002) but not during trial 1 (Ps >0.05).(J-L) The same measures and analysis as in G-I for 16-month-old mice.Gde2KO male and female mice were more active than WT mice during both trial 1 (ANOVA, effect of genotype F(1,≥23)>8.96,P<0.007) and trial 2 (ANOVA, effect of genotype F(1,≥23)>6.66,P<0.02).All graphs are means ± SEM; ns, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.See Table S1 for statistical details.Same measurements and analysis as in G and H for the total time spent in the center separated by sex (I) and its dynamics for males (J) and females (K) (also ns).(L-N) Total distance traveled (L), dynamics (M), and condensed dynamics (N) in the open arms of the plus maze.No effect of genotype or its interactions was detected (ANOVA, P>0.05).All graphs are means ± SEM; ns, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.See Table S1 for statistical details.All graphs are means ± SEM; ns, P > 0.05; *P < 0.05, **P < 0.01, and ***P < 0.001.See Table S1 for statistical details.

Fig. S7: Sex-separated analysis of Y Maze spatial preferences
(A-D) Spatial preference of WT and Gde2KO mice as measured by percent time spent in the novel and old arms at the 7-month time point.Total percent time spent in each arm separated by males (A) and females (C), and dynamics for males (B) and females (D).WT and Gde2KO mice of both sexes spent significantly more time in the novel arm compared to the old arm (ANOVA, effect of arm, F(1,≥10)>5.69,P<0.03) (E-H) The same measurements and analysis as in A-D, respectively, for 16-month-old mice.WT and Gde2KO mice of both sexes spent significantly more time in the novel arm compared to the old arm (ANOVA, effect of arm, F(1,≥11)>12.5,P<0.004).All graphs are means ± SEM; ns, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.See Table S1 for statistical details.All graphs are means ± SEM; ns, P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.See Table S1 for statistical details. (G-J) Analysis of context 2 fear acquisition and cued fear memory during trial 3 day 2. Percent time spent freezing during the delivery of the CS in trial 3 for males (G) and females (H).Male Gde2KO mice froze less than WT mice at the start of trial 3 (Fisher LSD post hoc, P<0.04).

Fig. S2 :
Fig. S2: Sex differences in Gde2KO hyperactivity phenotype (A-F) Analysis of distance traveled in OF test separated by sex.(A-C) Total distance (A) and

Fig. S3 :
Fig. S3: Sex differences in Gde2KO plus maze hyperactivity phenotype and condensed dynamic

Fig. S4 :
Fig. S4: Anxiety metrics in OF and plus maze

Fig. S5 :
Fig. S5: Differences in PPI are not explained by differences in startle response for Gde2KO animals

Fig. S6 :
Fig. S6: Sex separation and dynamics for social motivation measurements

Fig. S8 :
Fig. S8: Gde2KO mice learn new platform location during reversal days (A-C) Latency of training trials during the 4-day MWM task for WT and Gde2KO mice with sex combined (A), and separated by females (B) and males (C).(D-F) Analysis of the percent time

Fig. S9 :
Fig. S9: Sex-separated analysis of FC task (A-D) Analysis of context 1 fear acquisition and cued fear acquisition on trial 1 day 1 during FC